The existence of a number of pathologic syndromes depends on androgen hormones. Thus, growth of prostate cancer in early stages is androgen driven and can, at least temporarily, be stopped by androgen deprivation. Androgenic alopecia is caused by an unexplained switch from the growth promoting effect of androgens on the hair follicles to hair loss. In skin androgen mediated disorders, such as alopecia, acne vulgaris, and hirsutism, excess of the cutaneous androgens were shown to be the major nosological factor.
The androgenic hormones can act only via an androgenic receptor (AR), which is a transcription factor, a protein which interacts with a specific region of DNA. Thus, the mode of action of testosterone and its much more potent analog, 5-alpha dihydrotestoterone (DHT) depends upon binding to the AR. Only then can transcription by RNA polymerase II take place.
In the treatment of androgenic alopecia, various antiandrogens originally developed for the treatment of prostate cancer were claimed for systemic use, but side effects of chronic therapy with these systemically absorbable substances were of concern. In cutaneous afflictions topical anti-androgenic compositions have been tried, but with limited success, possibly because all non-steroidal compounds are resorbed by the skin and elicit systemic effects, which prevents their use in males. In the scalp, the precursors to androgens are normally converted into potent androgens, which bind to the AR in the hair follicles and promote hair growth. In genetically pre-disposed subjects however androgens at certain age cause hair loss. Clearly, a topically active composition capable of cutaneous, but not systemic resorption, and of suppressing or eliminating the AR locally, would be useful in preventing or reversing the incipient hair loss.
The current state of prostate cancer therapy (CaP), the second most prevalent malignancy in males, is unsatisfactory. When detected early, with the tumor strictly confined to the prostate gland, CaP can be often controlled by implantation of radioactive seeds, or by prostatectomy, which often results in incontinence and impotence. Locally advanced prostate cancer can often be reasonably controlled when in the pelvis and if encompassed into a single port of an external radiation beam.
For advanced CaP, the standard treatment is androgen receptor-blockade, usually in combination with LHRH superagonists, which suppresses both adrenal and testicular testosterone. The rationale of this approach is that early prostate cancer invariably depends on androgens for growth. The activity mechanism of clinically utilized antiandrogens is thought to involve blockade of the AR by binding to it and/or by interference with binding of the AR to the DNA; some agonistic compounds can even promote DNA binding but they do modify the binding domain. Thus, cyproterone acetate was found to block about 50% of AR binding to the DNA, while flutamide, bicalutamide or nilutamide, were found to completely block such binding. All of these state of the art compositions have nevertheless only limited applicability, as the primary tumor and its metastases eventually become refractory to further anti-androgenic therapy. The reason is invariably AR mutation, which can be occasionally found as a genetic deviation, but is usually a result of the AR blockade. Even when both suprarenal and testicular androgens are eliminated by chemical castration, LHRH super agonist and/or by surgical castration, the mutated receptor retains the capability to be activated by various steroidal metabolites and even progestins and estrogens. A variety of other factors can activate the androgen receptor gene via AR activation, such as insulin-like growth factor, epidermal growth factor, and keratinocyte growth factor and neuroendocrine transmitters, such as serotonin. Therefore, blocking the AR is not an ideal treatment and a new approach is needed. It has also been shown that as a result of the AR blockade, the AR gene is amplified with the resulting overproduction of the AR. In 6 to 24 months the AR mutates and the tumor and metastases became hormone refractory and continue to grow.
In selecting therapeutic options, a correct decision can only be made if the extent of the disease is known. When CaP is confined strictly to the gland, surgery and/or local or external radiation can be curative. However, in the case of extracapsular disease, prostatectomy or radiation are not only useless, but noxious, since a high rate of serious side effects, such as impotence, incontinence and chronic inflammation of the adjacent tissues accompanies these interventions. Members of the current diagnostic armamentarium comprise digital rectal palpation, serum prostate specific antigen determination and ultrasound, magnetic resonance or x-ray imaging. These techniques cannot detect CaP metastases to the lymph nodes and other soft tissues, resulting in clinical understaging of 40 to 60% of the patients.
The prior art of diagnostic localizing agents for CaP teaches specific radioactively labeled antibodies, but widespread use is limited by the complexity of the procedure. 5.alpha.-dihydrotestosterone labeled with .sup.18 F has been used for PET scanning, a generally inaccessible imaging modality.
There are substantial deficiencies in both therapeutic and diagnostic approaches to the treatment of CaP. It is therefore of interest to find compounds which not only block the AR, but also diminish the number of available ARs. Another desirable characteristic for topical purposes would be compounds which have low or no systemic resorption. Also, the compounds should degrade or be metabolized into components of low or no toxicity and have little or no anti-androgenic activity. In addition, radioisotope labeled compounds specific for neoplastic prostate cells would be of importance in order to visualize the pathomorphology of CaP accurately, so that unnecessary and costly surgery and/or radiation is avoided in patients where CaP has progressed beyond the reach of curative surgery or the scope of a single radiation port. Other appropriate therapies, such as androgen ablation and/or unspecific chemotherapy, can then be instituted.
Relevant Literature
U.S. Pat. No. 5,656,6651 and WO97/00071, and references cited therein, describe anti-androgenic directed compositions based on phenyldimethylhydantoins, where the phenyl group is substituted with a trifluoromethyl group and either a cyano or nitro group. See also, Battmann et al., J. Steroid Biochem. Molec. Biol. 64:103-111 (1998); Cousty-Berlin, ibid 51:47-55 (1994); and Battmann et al., ibid 48:55-60 (1994), for a description of analogous compounds and their activity. For other compounds having the substituted phenyl moiety, see U.S. Pat. Nos. 4,636,505 and 4,880,839, and EP 0 100 172. For discussions about the activities of antiandrogens, see Kuil and Brinkmann, Eur. Urol. 29:78-82 (1996); Kondo et al., Prostate 29:146-152 (1996), and Simard, et al., Urology 49:580-589 (1997). For discussions about alopecia and its relationship with androgens, see Kaufman, Dermatologic Clinics 14:697-711 (1996); Toney et al., J. Steroid Biochem. Molec. Biol. 60:131-136 (1997); Brouwer et al., J. of Dermatology 137:699-702 (1997); and Shapiro and Price Dermatologic Clinics 16:341-356 (1998).